Genipin alleviates vascular hyperpermeability following hemorrhagic shock by up-regulation of SIRT3/autophagy

Genipin (GP) is commonly used to treat cardiovascular diseases; however, the protective action of GP against vascular hyperpermeability (VH) has not been reported. We previously reported that intrinsic apoptotic signaling (IAS) is involved in VH following hemorrhagic shock (HS). GP inhibits apoptosis, but the specific mechanism remains unclear. In the present study, we observed that GP protects against HS-induced VH in vitro and in vivo. We report that this protective effect is related to the inhibition of IAS by up-regulation of autophagy via sirtuin 3 (SIRT3). The endothelial cell hyperpermeability induced by HS was enhanced by GP; this was attenuated by 3-methyladenine (3MA), a specific inhibitor of autophagy, indicating the involvement of autophagy. Consistent with these results, we found that 3MA reversed the effects of GP on up-regulation of autophagy, and also diminished the protective effect of GP against IAS activation following HS. Furthermore, knockout of SIRT3 inhibited GP-induced autophagy, indicating the requirement of SIRT3 in the regulation of autophagy by GP. In rats, GP improved HS-induced VH, which was repressed by 3MA and 3-(1H-1,2,3-triazol-4-yl)pyridine (3-TYP), a SIRT3 inhibitor. In conclusion, these findings suggest that autophagy plays a protective effect in VH following HS; the protective effect of autophagy is reinforced by GP, which protects against IAS and VH by up-regulating SIRT3.